Alessandro Corso

Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma

BACKGROUND Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. METHODS We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. RESULTS The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. CONCLUSIONS MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.

A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenströms macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

Better quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma

Background This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response. Design and Methods Patients (n=353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 for four cycles, and only on days 1–4 after the first four cycles). Time to response, duration of response, time-to-progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those of patients who had a partial response. Results At the time of unblinding, 32% of patients had achieved a complete or very good partial response and 28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48 months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached versus 44.2 months, P=0.021, respectively). The benefit of a complete or very good partial response was independent of when it was achieved. Conclusions Continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater clinical benefit over time for patients in this study.

High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program

Phase 2 trials have demonstrated that bortezomib ± dexamethasone is safe and effective in relapsed multiple myeloma (MM). In this multicentre, open‐label, phase 3b trial, 638 patients with relapsed or refractory MM (median 3 prior therapies) received bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11 of a maximum of eight 3‐week cycles (median 5 cycles). Dexamethasone 20 mg/d was added the day of and day after each bortezomib dose for progressive disease after ≥2 cycles or for stable disease after ≥4 cycles. Responses were assessed based on M‐protein changes. Overall response rate was 67%, including 11% complete (100% M‐protein reduction), 22% very good partial (75–99% reduction), 18% partial (50–74% reduction), and 16% minimal response (25–49% reduction). Dexamethasone was added in 208 patients (33%), of whom 70 (34%) showed improved response. Median time to best response of minimal response or better was 84 d. Most common grade 3/4 adverse events were thrombocytopenia (39%), neutropenia (16%), anaemia (12%), diarrhoea (7%), and peripheral neuropathy (6%). Neuropathy (any grade) was seen in 25% of the patients and led to discontinuation in 5%. Bortezomib, alone and combined with dexamethasone, is safe and effective in heavily pretreated patients with relapsed or refractory MM.

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw (ONJ) is a reported complication of bisphosphonate use. The incidence ranges between 6 and 13% and seems to be higher in people treated with zoledronic acid (ZA) than with pamidronate. We retrospectively evaluated the incidences of ONJ and skeletal-related events (SRE) in 106 patients with multiple myeloma divided in two groups according to the schedule of administration of bisphosphonates: 51 received monthly administrations until tolerated (group A, standard schedule), 55 were treated monthly during the first year and then every 3 months (group B, reduced schedule). The incidence of SRE was similar (15.1 per 100 person years in group A and 17.7 in group B). ONJ occurred in seven patients, six in group A and one in group B (P=0.049). The risk of ONJ was eight-fold lower with the reduced schedule than with the standard schedule. The only significant risk factor for ONJ was the type of bisphosphonate (P=0.006). The incidence of ONJ was significantly higher with ZA than with pamidronate + ZA (9.1 vs 1.6 per 100 person-years). No ONJ was observed in patients treated only with pamidronate. A reduced schedule of ZA may be safer than the standard schedule while maintaining anti-resorptive efficacy.

Bortezomib-induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients

Peripheral neuropathy (PN), with neuropathic pain as main symptom, represents the dose-limiting toxicity of the proteasome inhibitor bortezomib. Aim of this study was to compare the incidence, risk factors, severity and outcome of PN and neuropathic pain in patient treated with bortezomib up-front or at relapse. We studied 55 patients with multiple myeloma (MM) who received bortezomib as first line therapy and 70 pre-treated patients who received bortezomib in relapse or progression. Regarding PN, no differences were found among untreated and pre-treated patients in the incidence (55% vs 52%, p=0.43), severity (NCI grade 3-4 9% vs 14%, p=0.27), and outcome (improved/resolved 90% vs 91%, p=0.58). Concerning neuropathic pain, the incidence was lower (50% vs 81%, p=0.008) and solved earlier (35 days vs 91 days, p=0.02) in untreated compared with pre-treated patients. Untreated patients needed dose modification less frequently (36% vs 73%, p=0.012). No correlation was found between development of PN and prior exposure to potentially neurotoxic drugs such as thalidomide, vincristine, and cysplatin. Age represented the main risk factor for PN (p=0.036) with an increase in risk of PN amounting to 6% per year of age. In conclusion, incidence, severity and outcome of bortezomib-related PN are similar in untreated and pre-treated MM patients except for neuropathic pain which has lower incidence and shorter duration in untreated patients with less frequent need for bortezomib discontinuation. Age emerges as the most relevant risk factor for peripheral neuropathy, with a risk increase for PN of 6% per year of age.

Immune-mediated neuropathies in myeloma patients treated with bortezomib.

OBJECTIVE Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. METHODS Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. RESULTS Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin's lymphoma

PURPOSE Fludarabine phosphate is effective as a single agent in low-grade non-Hodgkins lymphoma (NHL). Combined with other antineoplastic agents it enhances the antitumor effect. Our aim was to define the therapeutic efficacy and toxicity of a combination of fludarabine, cyclophosphamide and dexamethasone (FluCyD) in patients with advanced low-grade lymphoma. PATIENTS AND METHODS Twenty-five adults with pretreated advanced-stage low-grade NHL were treated with three-day courses of fludarabine 25 mg/m2/day, cyclophosphamide 350 mg/m2/day, and dexamethasone 20 mg/day, every four weeks for a maximum of six courses. RESULTS Of the 25 patients, 18 (72%) responded, 8 (32%) achieving CR and 10 (40%) PR. Seven were failures. The median follow-up was 21 months (5-26). Eight CR patients remain in CR after 5-21 months. Of 10 PR patients, 3 are in continuous PR without further treatment after 12, 17 and 18 months. Myelosuppression was the most prevalent toxic effect. Although severe granulocytopenia (granulocyte count nadir < 500/microliter) and thrombocytopenia (platelet count nadir < 50,000/microliter) occurred in only 10% and 16% of courses, respectively, slow granulocyte or platelet count recovery caused delay of 40% of the courses. Nine patients (36%) required discontinuation of therapy because of persistent granulocytopenia and/or thrombocytopenia: three after one course, three after 2-4 courses, and three after five courses. Thirteen infectious episodes in 11 patients complicated 11% of courses. Two of 10 patients monitored for the circulating EBV load showed increased viral load. One of these developed aggressive lymphoma. CD4+ lymphocytes declined from a pre-therapy median value of 425/microliter to 141/microliter post-treatment (P = 0.001). Non-hematologic toxicities were rare and mild. CONCLUSIONS The combination of fludarabine with cyclophosphamide and dexamethasone is effective in pretreated advanced-stage low-grade NHL. It may broaden the range of therapeutic options in the salvage treatment of these patients. The main toxicity of this combination is prolonged myelosuppression that may cause treatment delay or withdrawal. The benefit of adding granulocyte colony-stimulating factor, particularly in patients with poor marrow reserve, needs to be investigated.

The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia clinical results in 46 patients

Background. Given the good penetration of systemic high‐dose cytarabine (HDara‐C) into the cerebrospinal fluid (CSF), this approach was used to treat patients with central nervous system (CNS) leukemia, either isolated or with concurrent extraneurologic disease (END).

Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis

Summary. Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long‐term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high‐risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets > 1000 × 109/l. From 1978 to 2000, with a median follow‐up of 10 years, 118 previously untreated high‐risk ET patients (median age 62 years, range 25–82), were treated with PB at the starting dose of 0·8–1 mg/kg/d. All patients reached a platelet count < 600 × 109/l and 91% achieved a platelet count < 400 × 109/l. During follow‐up, 13 patients had thrombosis, with a 10‐year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10‐year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1·1 (95% CI: 0·7–1·7), not statistically different from the general population (P = 0·54). Age was associated with a higher risk of death (P = 0·00009) and thrombosis (P = 0·003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow‐up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10‐year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.